STING activation promotes intestinal mucin secretion in IBD

Goblet cells produce mucus protecting the intestinal epithelium. Depleted goblet cells and a disrupted mucus layer are observed in inflammatory bowel diseases (IBD). Remarkably, both deficiency and overactivation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway lead to goblet cell depletion in mice. Here, we analyzed the role of cGAS-STING in goblet cell mucus regulation in IBD patients and human crypt-derived colonic organoids (HCO).

MUC and cGAS-STING pathway gene expression was analyzed in inflamed and non-inflamed mucosa (n = 821) of IBD patients and non-IBD controls, complemented by MUC2 and STING pathway (immune)histochemistry. HCO were exposed to the STING agonist diABZI and antagonist H151. STING pathway activation and MUC2 regulation were assessed by qPCR, Western blotting and immunofluorescence microscopy.

Gene expression of many mucins, including MUC2, and cGAS-STING pathway factors were enhanced in inflamed ileum and colon compared to non-inflamed mucosa. Histologically-recognizable (mucus-filled) goblet cells were reduced in inflamed IBD mucosa, yet de novo-synthesized immature MUC2 was readily detected alongside elevated levels of activated/phosphorylated STING. DiABZI dose-dependently enhanced p-STING in HCO, without affecting MUC2 gene expression. Mature MUC2 accumulated in the lumen of diABZI-treated HCO, reducing the number of MUC2-filled goblet cells, while immature MUC2 remained detectable, marking the abundant presence of goblet cells lacking mature MUC2. In contrast, H151 treatment did not reduce the number of mucus-filled goblet cells in HCO.

STING activation contributes to enhanced mucus release in inflamed IBD epithelium, providing a mechanistic explanation for the apparent histological depletion of goblet cells.